Abstract LB-015: Dissecting TGF beta-induced lethal EMT in Kras-driven pancreatic cancer

Abstract

Abstract Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is a devastating malignancy with an extremely poor prognosis. New insights are urgently needed into the tumorigenesis process and the tumor suppression mechanisms of pancreatic cancer. Genetic alterations in PDAC occur in a temporal sequence, usually initiating with activating mutations of the KRAS (~95%), and progressing by loss of tumor suppressors, including INK4A/ARF, TP53 and SMAD4/DPC4. Our recent work reveals that in mouse KrasG12D-driven PDAC cells, TGFβ induces a robust epithelial-to-mesenchymal transition (EMT) response, which leads to cell apoptosis. To determine the KrasG12D-dependent mechanism of priming pancreatic epithelial cells to be sensitive to TGFβ-induced lethal EMT, we utilize systematic approaches to integrate the transcriptome profile and Smad2/3 binding patterns to the genome to identify candidate mediators that regulate TGFβ-induced lethal EMT. To identify TGFβ gene response changes mediated by KrasG12D, we perform RNA-Seq analysis of inducible Tet-On KrasG12D pancreatic epithelial cells (PECs) treating with TGFβ or SB505124. Systematic analyses reveal that mutant KrasG12D, but not KrasWT, enables robust TGFβ gene responses of Snai1, Has2, Has3 and IL11. The massive induction of these genes is crucial for TGFβ-induced lethal EMT. Smad2/3 ChIP-Seq analysis reveals that transcription factor binding motifs of Rreb1 are specially associated with these KrasG12D-enhanced Smad2/3 binding sites. Furthermore, depletion of Rreb1 greatly impairs TGFβ-induced apoptosis. In summary, oncogenic KrasG12D drives a cell state change and sensitizes premalignant PECs to respond to TGFβ-induced lethal EMT. This function switch of TGFβ is potentially mediated through Kras-activated Rreb1 as a specific DNA binding partner of Smads. Citation Format: Jie Su. Mem. Dissecting TGF beta-induced lethal EMT in Kras-driven pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-015. doi:10.1158/1538-7445.AM2017-LB-015